Novel IC-IL33-Treg Axis in Kidney Immunosurveillance and Autoimmune Injury

Background: Various autoimmune diseases are frequently associated with Acute Kidney Injury (AKI). The underlying patho-mechanisms are complex and varied, involving autoantibodies and cellular immune responses that mediate renal injury. Intercalated cells (ICs), which are involved in proton secretion in the renal tubules, may also be key players in initiating immune responses within the kidney. These cells are strategically positioned at the interface between the renal epithelial barrier and the immune system, making them well-suited to sense and respond to stress signals. This study explores the molecular mechanisms by which ICs communicate with immune cells to maintain renal immune homeostasis and contribute to autoimmune manifestations. Methods: We depleted Foxp3+ regulatory T cells (Tregs) by injecting (i.p.) diphtheria toxin (DT) into male and female Foxp3-DTR mice. We analyzed, 2 weeks post-depletion, the renal immune responses using flow cytometry, ELISA of urine and serum autoantibodies, confocal microscopy, and functional kidney assessments. RNA sequencing of ICs was performed to identify molecular pathways. Results: Treg depletion triggered autoimmune inflammatory responses characterized by aggravated immune cell infiltration (neutrophils, macrophages, T and B cells), formation of B cell clusters, and enhanced antigen presentation. We observed elevated renal IgG, IgM, IgA, IgG1, and IgG2c autoantibodies in urine and serum, and antibody deposition in glomeruli and around tubules. Kidney damage was evidenced by reduced glomeruli size, proximal tubular injury, increased urine albumin/creatinine ratio, and reduced urine output. Tolerance disruption induced IC upregulation of inflammasome-related genes and IL-33, a key alarmin that signals damage and activates tissue Tregs. Despite initial Treg depletion, we observed a notable Treg rebound with enhanced presence of activated CD69+ Tregs. Conclusion: Our findings reveal novel positive IC-Treg crosstalk through the IL-33 pathway, identifying immunoregulatory mechanisms that maintain renal immune tolerance. The identification of a specific AKI subgroup and its molecular mechanisms offers potential targets for developing therapeutic strategies against autoimmune kidney injury. Funding: Other NIH Support - NICHD